RU2126008C1 - Diazabicycloalkene derivatives and pharmaceutical composition - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to derivatives of diazabicycloalkenes of the formula (I)

where R¹ means a group of the formula (II)

or (III)

; R¹¹ and R¹² - lower alkyl or taken together they form lower alkylene group; R¹³ - hydroxyl, lower acyloxy-group; R¹⁴ - hydrogen atom or lower alkyl; A - nitrogen atom or C-R¹⁶ where R¹⁶ - hydrogen, cyano-, nitro-, trifluoromethoxy-, penta- -fluoroethyl-, sulfonyl-group possibly substituted with aryl, carbamoylethyl- or sulfamoyl-group; R¹⁵ - hydrogen, nitro-group; R²¹ and R²² - lower alkyl; R²³ - hydroxyl; R²⁴ and R²⁵ - hydrogen; X - oxygen or N-R³¹ where R³¹ - hydrogen; R² - hydrogen alkenyl, alkynyl, alkyl; or R² - optionally substituted alkylphenyl; R³ and R⁴ - hydrogen or alkyl; n = 1, or their pharmaceutically acceptable salts. Compounds of the formula (I) show an excellent activity enhancing potassium exchange by potassium channel opening. EFFECT: enhanced effectiveness of compounds synthesized. 9 cl, 13 tbl, 47 ex

Description

 The invention relates to a new diazabicycloalkene compound, which has excellent potassium metabolism increasing activity by opening potassium channels and to therapeutic agents for treating hypertension, angina pectoris and asthma, which contain a diazabicycloalkene compound as an active agent.

 The treatment of hypertension (hypertomy) is carried out, supporting the patient with antihypertensive drugs for a long time, and therefore not only the requirements of powerful antihypertensive activity are presented to antihypertensive drugs, but also the absence of undesirable side effects during prolonged use. Thus, antihypertensive drugs have the following requirements: 1) they must have a potential and long-lasting antihypertensive activity, 2) they must detect a slow onset of antihypertensive action, since the rapid onset of this action significantly changes the homeostasis of the circulatory organs (Life Science, Vol. 47, p. 1693 - 1705 (1990)), which easily cause a reflex of tachycardia (Japanese Journal of Pharmacology, Vol. 58 (Suppl.I), p. 36 (1992)), and it is desirable 3) to increase renal blood flow, since impaired blood flow in close kidney o is associated with the preservation and development of hypertension and an increase in renal blood flow thus facilitates hypertension (Circulation, Vol. 69, p. 1142 - 1145 (1984)).

где R представляет атом водорода, алкильную группу, арильную группу, аралкильную группу и т.д., и известно, что обладает мощной и продолжительной антигипертензивной активностью, приписываемой активации калиевых каналов и поэтому пригодное в качестве антигипертензивного лекарства (JP-A-2-145584, JP-A-3-20275 и Journal of Medicinal Chemistry Vol. 33, с. 2759 - 2767 (1990)); термин "JP-A", как он используется здесь, обозначает опубликованную, не прошедшую экспертизу японскую заявку.A compound represented by the general formula is known

where R represents a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, etc., and it is known to have powerful and long-lasting antihypertensive activity attributed to activation of potassium channels and therefore suitable as an antihypertensive drug (JP-A-2-145584 , JP-A-3-20275 and Journal of Medicinal Chemistry Vol. 33, pp. 2759-2767 (1990)); the term “JP-A,” as used herein, refers to a published, unexamined Japanese application.

 Although the compounds of formula IV almost satisfy the requirements for the strength and duration of antihypertensive activity, they remain unsatisfactory in terms of the nature of the onset of antihypertensive action and increased activity of the renal blood flow.

 The aim of the invention is to provide a compound that has potent and long-lasting antihypertensive activity, shows a slow onset of action, and also exhibits excellent activity in increasing renal blood flow.

 Another objective of the invention is the provision of pharmaceutical preparations containing the compound.

 Various diazabicycloalkene compounds were obtained and their pharmacological activity was studied. It was found that the diazabicycloalkene compound of formula I shown below has excellent potassium metabolism increasing activity and strong and long-lasting antihypertensive activity with a slow onset of action and is highly active for increasing renal blood flow and therefore suitable as an agent for treating hypertension. It was also found that the compound of formula I is suitable as an agent for the treatment of other diseases caused by narrowing of blood vessels or smooth bronchial muscles, such as angina pectoris and asthma. The invention is based entirely on these studies.

где R¹ представляет группу формулы (II) или (III)

где R¹¹ и R¹² каждый представляет низшую аклильную группу, или взятые вместе образуют низшую алкеновую группу;
R¹³ представляет гидроксильную группу, низшую алкоксигруппу или низшую ацилоксигруппу;
R¹⁴ представляет атом водорода или низшую алкильную группу;
A представляет атом азота или C-R¹⁶;
R¹⁵ и R¹⁶ каждый представляют атом водорода, атом галоида, цианогруппу, нитрогруппу, трифторметоксигруппу, пентафторэтильную группу, низшую алкильную группу, низшую алкенильную группу, низшую алкинильную группу, низшую ацильную группу, карбоксильную группу, низшую алкоксикарбонильную группу, карбомоильную группу, которая может быть замещена низшей алкильной группой, содержащей 1-2 атома углерода, сульфинильную или сульфонильную группу, которая может быть замещена низшей алкильной, низшей алкокси, арильной или арилоксигруппой или сульфамоильную группу, которая может быть замещена низшей алкильной группой, содержащей 1-2 атома углерода;
R²¹ и R²² каждый представляют низшую алкильную группу или взятые вместе, образуют низшую алкиленовую группу;
R²³ представляет гидроксильную группу, низшую ацилоксигруппу или низшую алкоксигруппу;
R²⁴ представляет атом водорода или низшую алкильную группу;
R²⁵ представляет атом водорода, низшую алкильную группу, низшую алкенильную группу, низшую алкинильную группу, аралкильную группу или аралкильную группу, содержащую по крайней мере один гетероатом при арильной части;
X представляет атом кислорода, атом серы или N-R³¹, где R³¹ представляет атом водорода, низшую алкильную группу, низшую алцильную группу или аралкильную группу;
R² представляет атом водорода, низшую алкенильную группу, низшую алкинильную группу, замещенную или замещенную низшую алкильную группу, замещенную или незамещенную арильную группу, замещенную или незамещенную аралкильную группу, или аралкильную группу, содержащую по крайней мере один гетероатом в арильной части;
R³ и R⁴ каждый представляют атом водорода или атом галоида или низшую алкильную группу;
n = 1 или 2.The invention relates to a diazabicycloalkene compound of the formula

where R ¹ represents a group of formula (II) or (III)

where R ¹¹ and R ¹² each represents a lower acyl group, or taken together form a lower alkenyl group;
R ¹³ represents a hydroxyl group, a lower alkoxy group or a lower acyloxy group;
R ¹⁴ represents a hydrogen atom or a lower alkyl group;
A represents a nitrogen atom or CR ¹⁶ ;
R ¹⁵ and R ¹⁶ each represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethoxy group, a pentafluoroethyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower acyl group, a carboxyl group, a lower alkoxycarbonyl group, a carbomoyl group which may be substituted by a lower alkyl group containing 1 to 2 carbon atoms, a sulfinyl or sulfonyl group, which may be substituted by a lower alkyl, lower alkoxy, aryl or aryloxy group or sulfam yl group which may be substituted with a lower alkyl group containing 1-2 carbon atoms;
R ²¹ and R ²² each represent a lower alkyl group or, taken together, form a lower alkylene group;
R ²³ represents a hydroxyl group, a lower acyloxy group or a lower alkoxy group;
R ²⁴ represents a hydrogen atom or a lower alkyl group;
R ²⁵ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aralkyl group or an aralkyl group containing at least one heteroatom in the aryl part;
X represents an oxygen atom, a sulfur atom or NR ³¹ , where R ³¹ represents a hydrogen atom, a lower alkyl group, a lower alkyl group or an aralkyl group;
R ² represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group, a substituted or substituted lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or an aralkyl group containing at least one heteroatom in the aryl part;
R ³ and R ⁴ each represent a hydrogen atom or a halogen atom or a lower alkyl group;
n = 1 or 2.

 The invention also relates to treatment agents and compositions for the treatment of hypertension and angina pectoris or asthma, which contain a diazabicycloalkene compound of formula (I) as an active ingredient.

 In the formula (I) and in the subsequent discussion of the formula (I), each of these groups is an unsubstituted group, unless otherwise specified specifically for the inclusion of substituted groups.

 The various groups mentioned in formula (I) are described in further detail below.

 A “lower alkyl group” includes straight or branched chain alkyl groups having from 1 to 6 carbon atoms, for example a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and a tert-butyl group.

 A "lower alkenyl group" includes straight or branched alkenyl groups containing from 2 to 6 carbon atoms, for example a vinyl group or a propynyl group.

 A “lower alkynyl group” includes straight or branched alkynyl groups containing from 2 to 6 carbon atoms, for example an ethynyl group, a 1-propynyl group and a 2-propynyl group.

 A "lower alkylene group" includes those groups which contain from 2 to 6 carbon atoms, for example a propylene group, a butylene group, a pentylene group and a hexylene group.

 An “aralkyl group” includes a benzyl group, a phenylethyl group and a naphthylmethyl group.

 "Aralkyl group containing at least one heteroatom in the aryl part" includes a 5 or 6 membered heterocyclic ring containing at least one heteroatom (preferably 1-3 heteroatoms) selected from the group comprising a nitrogen atom, an oxygen atom or a sulfur atom, the ring of which is bonded to an alkylene group containing from 1 to 4 carbon atoms. A ring may contain, for example, from one to three nitrogen atoms. Specific examples of these groups include pyridylmethyl, piridiletilnaya, pirimidilmetilnaya, pirimidiletilnaya, piperazinilmetilnaya, piperaziniletilnaya, triazinilmetilnaya, triaziniletilnaya, pirazolilmetilnaya, pirazoliletilnaya, pirazolilpropilnaya, imidazolylmethyl, imidazoliletilnaya, imidazolilpropilnaya, oxazolylmethyl, oksazoliletilnaya, oksazolilpropilnaya, thiazolylmethyl, thienylmethyl, and aziridinilmetilnaya aziridiniletilnaya group.

 An “aryl group” includes a phenyl group, a naphthyl group and a biphenyl group.

 A "lower alkoxy group" includes groups that contain from 1 to 4 carbon atoms, for example, a methoxy group, an ethoxy group, a propoxy group and a butoxy group.

 A "lower acyl group" includes groups that contain from 1 to 8 carbon atoms, for example a formyl group, an acetyl group, a propanoyl group and a butanoyl group.

 A "lower acyloxy group" includes groups that contain from 1 to 8 carbon atoms, for example a formyloxy group, an acetoxy group, a propanoyloxy group, and a butanoyloxy group.

 A "lower alkoxycarbonyl group" includes groups that contain from 2 to 6 carbon atoms, for example a methoxycarbonyl group, an ethoxycarbonyl group and a propoxycarbonyl group.

 A “sulfinyl group which may be substituted with a lower alkyl group”, i.e. a lower alkylsulfonyl group, includes groups that contain from 1 to 5 carbon atoms, for example a methylsulfinyl group, an ethylsulfinyl group and a propylsulfinyl group.

 A "sulfonyl group", which may be substituted with a lower alkyl group, "i.e., a lower alkylsulfonyl group, includes groups that contain from 1 to 5 carbon atoms, for example a methylsulfonyl group, an ethylsulfonyl group and a propylsulfonyl group.

 A "sulfonyl group" which may be substituted with a lower alkoxy group, "i.e., a lower alkoxy sulfonyl group, includes groups that contain from 1 to 5 carbon atoms, for example, a methoxysulfonyl group, an ethoxysulfonyl group and a propoxysulfonyl group.

 A “sulfonyl group which may be substituted with a lower alkoxy group” includes groups that contain from 1 to 5 carbon atoms, for example, a methoxysulfinyl group, an ethoxysulfinyl group or a propoxysulfinyl group.

 A “sulfonyl group which may be a substituted aryl group” includes a phenylsulfonyl group and a naphthylsulfonyl group.

 A “sulfinyl group which may be a substituted aryl group” includes a phenylsulfenyl group and a naphthylsulfinyl group.

 A "sulfonyl group", which may be a substituted aryloxy group "includes a phenyloxy sulfonyl group and a naphthyloxy sulfonyl group.

 A “sulfinyl group which may be substituted with an aryloxy group” includes a phenyloxy sulfinyl group and a naphthyloxy sulfinyl group.

 A “halogen atom” includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

When R ² represents a substituted lower alkyl group, representative examples thereof include a formyl substituted lower alkyl group, a carboxyl substituted lower alkyl group, a hydroxyl substituted lower alkyl group, a lower alkoxy substituted lower alkyl group, a lower acyl substituted lower alkyl group, a lower alkoxycarbonyl lower group a lower acyloxy-substituted lower alkyl group, a halo-substituted lower alkyl group, a nitro substituted lower alkyl group, a cyano-substituted lower alkyl group, lower alkylsulfonyl substituted-lower alkyl group, lower alkylsulfinyl substituted-lower alkyl group, arylsulfonyl substituted lower alkyl group, arylsulfonyl substituted lower alkyl group, sulfamoyl substituted lower alkyl group, mono-substituted lower alkyl group, mono-substituted lower alkyl group lower alkyl group, carbamoyl-substituted lower alkyl group, mono-lower alkylcarbamoyl-substituted lower alkyl group, di-lower carbamoyl substituted-lower alkyl group, amino-substituted-lower alkyl group, mono-lower alkylamino-substituted-lower alkyl group, di-lower alkylamino-substituted-lower alkyl group, mercapto-substituted-lower alkyl group, lower alkylthio-substituted lower alkyl group, arylthio-substituted lower alkyl group an acrylamide substituted lower alkyl group; and a trifluoromethoxy substituted lower alkyl group.

When R ² represents a substituted aryl group, representative examples thereof include a formylaryl group, a carboxyaryl group, a lower alkoxyaryl group, a lower acylaryl group, a lower alkoxycarbonylaryl group, a lower acyloxyaryl group, a haloaryl group, a nitroaryl group, a cyanoaryl group, a lower alkylsulfonylaryl group , arylsulfonylaryl group, arylsulfonylaryl group, sulfomoylaryol group, mono-lower alkylsulfamoylaryl group y, di-lower alkylsulfamoylaryl group, carbomoylary group, mono-lower alkylcarbamoylaryl group, di-lower alkylcarbamoylaryl group, aminoaryl group, mono-lower alkylaminoaryl group, di-lower alkylaminoaryl group, mercaptoaryl group, lower alkylarylaryl group, lower alkylarylaryl group a group and a trifluoromethoxyaryl group.

When R ² is a substituted aralkyl group, representative examples thereof include those which contain an aryl part substituted by a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a cyano group, a lower acyl group, a lower alkoxycarbonyl group, a nitro group, a trifluoromethoxy group, a lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkoxysulfonyl group, lower alkoxysulfonyl group, carbomoyl group, mono-lower alkylcarbamoyl th group, di-lower alkyl carbamoyl group, sulfamoyl group, mono- or di-lower alkyl sulfamoyl group or carboxyl group.

 The compound of formula (1) can be converted in the usual way into a pharmaceutically acceptable salt by treatment with an inorganic acid (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid or nitric acid) or an organic acid (e.g. acetic acid, propionic acid, succinic acid, glycolic acid, lactamic acid, maleic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid Slots or ascorbic acid) or to a hydrate or various solvates.

Compounds of formula (I) in which R ¹ represents a group of formula (II) are preferred. In the formula (II), R ¹¹ and R ¹² each represents preferably a methyl group; R ¹³ represents preferably a hydroxyl group or a lower acyloxy group; R ¹⁴ represents preferably a hydrogen atom or a methyl group; R ¹⁵ is preferably a hydrogen atom and A is preferably CR ¹⁶ , where R ¹⁶ is preferably a cyano group, a nitro group or a pentafluoroethyl group.

R ² represents preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, a 2-propyl group, a 2-propynyl group, an isobutyl group, an allyl group, an unsubstituted benzyl group, or a benzyl group containing, as a substituent, a lower alkyl group containing from 1 to 4 carbon atoms, a halogen atom, an alkoxy group or a cyano group attached to the phenyl part of the benzyl group.

R ³ and R ⁴ each represent preferably a hydrogen atom. X is preferably an oxygen atom, n is preferably 1.

 The compounds of formula (I) each include optical isomers represented by formulas (Ia) to (Id) shown below, referred to asymmetric carbon atoms.

где R², R¹³, R¹⁴, R¹⁵, A, X и n имеют вышеуказанные для формулы I значения.

where R ² , R ¹³ , R ¹⁴ , R ¹⁵ , A, X and n are as defined above for formula I.

These optically active compounds and mixtures thereof are also included in the scope of the present invention. Particularly preferred optically active compounds are those represented by formulas Ia or Ib. For example, the compound obtained in example 21, as described below, is included in formula (Ia). Particularly preferred mixtures of optically active compounds are a racemic mixture of a compound of formula (Ia) and a compound of formula (Ic), and a racemic mixture of compound (Ib) and a compound of formula (Id), where R ² , R ¹³ , R ¹⁴ , R ¹⁵ , A , X and n represent values as defined above in formula (I).

 Specific examples of the compounds of formula (I) are shown below.

1) 3,4-trans-4- / 3-benzyl-2-oxo-3,4-diazabicyclo / 4.1.0 / -hept-4-en-5-yloxy / -3,4-dihydro-2,2 -dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile:
racemate (Ia) and (Ic) or racemate (Ib) and (Id), where R ² = benzyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0 .

2) 3,4 - trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-ene -5-yloxy / -2H-1-benzopyran-6-carbonitrile:
racemate (Ia) and (Ic) or racemate (Ib) and Id), where
R ² = CH ₃ , R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

4) /3S, 4R,1'S,6'R/-4-/3-бензил-2-оксо-3,4-диазабицикло/4.1.0/гепт- 4-ен-5-илокси/-3,4-дигидро-2,2-диметил-3-гидрокси-2H-1-бензопиран-6- карбонитрил:
оптически активное соединение (Ia), где R²=бензил, R¹³=OH, R¹⁴, R¹⁵=H, A=C-CN, n=1 и X=0.3) 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-ene -5-yloxy / -2H-1-benzopyran-6,7-dicarboxyimide:
racemate (Ie) and (Ig) or racemate (If) and (Ih):

4) / 3S, 4R, 1'S, 6'R / -4- / 3-benzyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -3,4- dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia), where R ² = benzyl, R ¹³ = OH, R ¹⁴ , R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

5) / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1 .0 / hept-4-en-5-yloxy / -2H- 1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = CH ₃ , R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

6) / 3S, 4R, 1'R ^* , 6'S ^* / -4- / 3-allyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -3, 4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = allyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

7) / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 2-oxo-3- / 2-propin-1-yl / -3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = 2-propin-1-yl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

8) / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 3- / 2-methoxyethyl / -2-oxo-3,4 -diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = 2-methoxyethyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

9) / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 3- / 2-hydroxyethyl / -2-oxo-3,4 -diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = 2-methoxyethyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

10) / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 3-isobutyl-2-oxo-3,4-diazabicyclo / 4.1 .0 / hept-4-en-5-yloxy / -2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = isobutyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

11) / 3S, 4R, 1'R ^* , 6'S ^* / -4- / 3-n-butyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / - 3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = n-butyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

12) / 3S, 4R, 1'R ^* , 6'S ^* / -4- / 3- / 2-chlorobenzyl / -2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = 2-chlorobenzyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

13) / 3S, 4R, 1'R ^* , 6'S ^* / -4- / 3- / 2,6-dichlorobenzyl / -2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5 -yloxy / -3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = 2,6-dichlorobenzyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

14) / 3S, 4R, 1'R ^* , 6'S ^* / -4- / 3- / 2,4-dichlorobenzyl / -2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5 -yloxy / -3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = 2,4-dichlorobenzyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

15) / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 3- / 2-methylbenzyl / -2-oxo-3,4 -diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = 2-methylbenzyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

16) / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 2-oxo-3,4-diazabicyclo / 4.1.0 / hept -4-en-5-yloxy / -2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = H, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

17) / 3S, 4R, 1'R ^* , 6'S ^* / -4- / 3-cyanomethyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -3, 4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = cyanomethyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

18) / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-4- /3-ethoxycarbonyl-methyl-2- oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -3-hydroxy-2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = ethoxycarbonylmethyl, R ¹³ = OH, R ¹⁴ = R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

19) / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-3-hydroxy-4- /3-methyl-2- oxo-3,4-diazabicyclo / 4.1.0/hept-4 en-5-yloxy / -2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile:
optically active compound (Ia) or (Ib), where R ² = R ¹⁴ = CH ₃ , R ¹³ = OH, R ¹⁵ = H, A = C-CN, n = 1 and X = 0.

где R², R³, R⁴, R¹¹, R¹², R¹⁴, R¹⁵, R²¹, R²², R²⁴, R²⁵, n и A имеют вышеуказанные в формуле I значения.Compounds of the invention can be obtained by methods (a) to (c)
Method (a)

where R ² , R ³ , R ⁴ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , R ²¹ , R ²² , R ²⁴ , R ²⁵ , n and A are as defined above in formula I.

 (Compound (Ii) or compound (Ij) can be prepared by reacting compound (V) with compound (VIa) or compound (VII), respectively.

The reaction is usually carried out in an inert solvent, such as a lower aliphatic alcohol (e.g. methyl alcohol or ethyl alcohol), acetonitrile or dimethylformamide (DMF), preferably in ethyl alcohol or DMF, in the presence of an organic base (e.g. pyridine) or inorganic base (e.g. sodium hydroxide or potassium carbonate), preferably pyridine, as a catalyst at 50-150 ^o C, preferably 80-110 ^o C, for 5-48 hours, preferably 10-20 hours

 Depending on whether the starting compound (VIa) or (VII) is a racemate or an optically active compound, the resulting compound (Ii) or (Ij) will be a racemate or an optically active compound.

где R², R³, R⁴, R¹¹, R¹², R¹⁴, R¹⁵, n и A представляют значения, как они определены выше в формуле (I).The racemate of compound (VIa) can be obtained in a known manner (JP-A-52-122372 or JP-A-61-293984). Compounds (VIa), compound (VIb) having a (3S, 4S) configuration can be prepared in a known manner (YP-A-2-42074 or Journal of Medicinal Chemistry, Vol. 34, p. 3074 (1991)). Based on the optically active compound (VIb) shown below, a compound of formula (Ik) is prepared as follows:

where R ² , R ³ , R ⁴ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , n and A represent the values as defined above in formula (I).

 Compound (Ii) obtained using compound (VIa) includes 4 optical isomers assigned to the trans configuration at the position of the 3,4-pyran ring and the cis-α or β configuration of hydrogen atoms associated with the 1 and 6-positions of the diazabicycloalkene ring . Four optical isomers make up two pairs of diastereomers. The racemates of each of the two pairs of diastereomers can be easily separated chromatographically on a silica gel column.

 Compound (Ik), which is prepared using compound (VIb), includes 2 diastereomers assigned to the configuration of hydrogen atoms associated with the 1- and 6-positions of the diazabicycloalkene ring. Two diastereomers can be easily separated on a silica gel chromatography column.

 Compound (V), which is used in the reaction scheme above, is prepared by reacting compound (VIII) shown below with a hydrazine derivative in a lower aliphatic alcohol (e.g. methyl alcohol or ethyl alcohol), acetonitrile, acetic acid, etc.

где R², R³, R⁴ и n представляют значения, как определено выше в формуле (I).

where R ² , R ³ , R ⁴ and n represent values as defined above in formula (I).

 Compound (VIII) is obtained by a method known in the literature. For example, compound (VIII), where n = 1 is obtained according to Justus Liebigs Annalen der Chemie, Vol. 606, p. 1 (1957), Tetrahedron Letters, Vol. 21, p. 1847 (1978) or in print, Vol. 28, p. 267 (1987) and compound (VIII), where n = 2 is obtained according to Tetrahedron Letters, Vol. 28, p. 267 (1987).

It is possible to replace the substituent R ² in a particular compound of formula (V) with other desired substituents in a known manner, for example by catalytic reduction or dealkylation.

где R², R³, R⁴, R¹¹, R¹², R¹⁴, R¹⁵, R²¹, R²², R²⁴, R²⁵, n и A имеет вышеуказанные для формулы I значения.Method b

where R ² , R ³ , R ⁴ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , R ²¹ , R ²² , R ²⁴ , R ²⁵ , n and A have the meanings given above for formula I.

 Compound (Il) or (Im) can be prepared by reacting compound (IX) with compound (VIa) or (VII).

The reaction is carried out in an inert solvent such as a lower aliphatic alcohol (e.g. methyl alcohol or ethyl alcohol), acetonitrile or DMF, preferably DMF, in the presence of an organic base (e.g. pyridine) or an inorganic base (e.g. sodium hydroxide or potassium carbonate, or sodium hydride), preferably sodium hydride as a catalyst at 20-150 ^° C, preferably 50-110 ^° C, for 5-48 hours, preferably 10-20 hours

 Compound (IX) can be obtained in a known manner (Journal of Hetero-chemical Chemistry, Vol. 21, p. 961 - 968 (1984), Journal of Organic Chemistry, Vol. 36, p. 3356 - 3361 (1971) or Chemische Berichte, Vol .100, p. 2719 - 2729) (1967)).

 Similar to method (a), wherein the starting compound (VIa) or (VII) representing a racemate or an optically active compound determines whether the final compound (Il) or (Im) is a racemate or an optically active compound. Using the racemate as the starting compound, the final compound (Il) includes 4 optical isomers related to the trans configuration of the 3,4-position of the pyran ring and the cis-α or β / configuration of hydrogen atoms bonded to the I ′ and 6 ′ positions diazabicycloalkene ring. Four optical isomers consist of two pairs of antipodes. The racemates of each of the two pairs of antipodes can be easily separated chromatographically on a silica gel column.

 On the other hand, the compound obtained from compound (VIb) includes 2 diastereomers assigned to the configuration of hydrogen atoms bonded to the 1 ′ and 6 ′ positions. The two diastereomers can be easily separated using a silica gel chromatography column.

In each of methods (a) and (b), the substituent R ^{2 of the} final compound can be replaced, if desired, with another substituent known in the art. For example, a compound where R ² represents a hydrogen atom can be obtained from the corresponding compound, where R ² represents a commonly used liberated group, for example an n-methoxybenzyl group, by reaction with a liberating reagent, for example 2,3-dichloro-5,6-dicyano -1,4-benzoquinone (DDBH). In addition, a compound where R ² represents a hydrogen atom can be converted to the corresponding compounds having various substituents, such as R ² , by reaction with various halogen compounds.

где R², R³, R⁴, R¹¹, R¹², R¹⁴, R¹⁵, X, A и n представляют значения, как они определены выше в формуле (I);
R¹⁷ представляет низшую алкильную группу;
R¹⁸ представляет атом водорода или низшую алкильную группу;
V представляет атом галоида.Method (c):

where R ² , R ³ , R ⁴ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , X, A and n are values as defined above in formula (I);
R ¹⁷ represents a lower alkyl group;
R ¹⁸ represents a hydrogen atom or a lower alkyl group;
V represents a halogen atom.

That is, the compound (Io) is obtained by reacting the compound (In) obtained by the method (a) or (b) with an acylating agent in accordance with the method disclosed in JP-A-3-20275. Suitable acylating agents that can be used include preferably lower alkyl carboxylic acid anhydrides, lower alkyl carboxylic acid halides and formic acid. The acylation reaction is carried out in an inert solvent (e.g. methylene chloride, tetrahydrofuran (THF) or (DMF), preferably methylene chloride, in the presence of an inorganic base (e.g. potassium carbonate) or an organic base (e.g. pyridine or triethylamine), preferably triethylamine, as a catalyst in 20 to 150 ^o C, for 1 to 48 hours, preferably 3 to 20 hours

In the method (c), where the compound (Ij) or (Im) is used as the starting compound, the compounds of formula (I) are obtained, where R ¹ has the structure of formula (III).

 The compound of the present invention can be obtained as pure optical isomers by methods (a) to (c), where an optically active compound or racemate is used as the starting compound, and the resulting isomeric mixture is separated by an appropriate combination of isolation methods, such as column chromatography, optical resolution using optical resolving agents, using the differences in the two diastereomers for solubility in the solvent and high pressure liquid chromatography.

 The compounds of formula (I) are sometimes isolated in the form of a hydrate or solvate or as an amorphous compound, and all these modifications are included in the scope of the present invention.

 Thus, the compound of formula (I) has excellent potassium metabolism increasing activity and is therefore effective in treating various diseases caused by narrowing of blood vessels, smooth bronchial muscles, etc., for example, coronary heart disease, an example of which is angina pectoris, asthma, pollakiuria, complication of subarachnoid hemorrhage, peripheral arterioinfarction, etc. The compound has a potential and long-lasting antihypertensive activity with a slow onset of action and shows excellent activity in increasing renal blood flow. In addition, the compound has high stability. Thus, the compound is particularly useful as an agent for the treatment of hypertension.

 The compound of the present invention can be administered orally or non-orally in any desired dosage form, such as tablets, granules, powders, capsules, solutions, syrups, oily or aqueous suspensions, and the like. In the preparation of dosage forms and compositions containing the compound, commonly used binders or adjuvants, such as lubricants, solvents, and surfactants, may be added.

 Typically, the dose of the compound is 0.001-1.0 mg, more preferably 0.01-0.5 mg per day per adult, by oral administration, although to some extent the changes depend on the route of administration, symptoms and period of use.

 The present invention will be illustrated in more detail with respect to comparative examples, examples and control examples, but it is understood that the present invention is not limited to these examples.

 Reference Example 1. (±) -3-benzyl-3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione.

 42 g (374 mmol) of 1,2-cyclopropanedicarboxylic acid anhydride are dissolved in 150 ml of acetonitrile, and a solution of 45.8 g (374 mmol) of benzylhydrazine in 50 ml of acetonitrile is added dropwise to the solution, and the mixture is heated under reflux for 15 hours The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography. Crystallization of their ethyl acetate gives 24.1 g (29.7%) of the title compound.

Melting point: 186 - 188 ^o C.

NMR (CDCl ₃ , TMS) δ ppm: 1.15 (1H, m), 1.69 (1H, m), 2.10 (1H, m), 2.28 (1H, m), 4 66 (1H, d, J = 15.6 Hz), 4.84 (1H, d, J = 15.6 Hz), 7.32 (5H, s).

 Reference examples 2 to 24. The compounds shown in table. 1 below, obtained in the same way? as in reference example 1.

 Reference Example 25. (±) -3,7,7-trimethyl-3,4-diazabicyclo / 4.1.0/heptane-2,5-dione.

 In 5 ml of ethyl alcohol, 949 mg (6.77 mmol) of 3,3-dimethyl-1,2-cyclopropanedicarboxylic acid anhydride and 0.36 ml (6.77 mmol) of methylhydrazine are added and the mixture is heated under reflux for 16 hours. The solvent removed by distillation under reduced pressure, the residue was purified by chromatography on a silica gel column. Recrystallization from ethyl acetate / hexane gave 312 mg (27.3%) of the title compound.

Melting point: 151 - 154 ^o C.

NMR (CDCl ₃ , TMS) δ (ppm): 1.21 (3H, s), 1.34 (3H, s), 1.98 (1H, d, J = 7.3 Hz), 2 10 (1H, d, J = 7.3 Hz); 3.24 (3H, s).

 Reference Example 26. (±) -3- (4-hydroxybenzyl) -3,4-diazabicyclo (4.1.0) heptane-2,5-dione.

 To 5 ml of methylene chloride add 462 mg (1.87 mmol) of (±) -3- / 4-methoxybenzyl / -3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione obtained in comparative example 19. The mixture cooled in a dry ice / methanol bath and then 0.1 ml (1.1 mmol) of tribromidator are added dropwise. The temperature was raised to room temperature and the mixture was stirred for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was recrystallized from ethanol / chloroform to obtain 120 mg (29.6%) of the title compound.

NMR (DMCO-d ₆ , TMS) δ (ppm): 0.87 - 0.91 (1H, m), 1.56 - 1.62 (1H, m), 1.97 - 2.02 (1H, m), 2.07 - 2.12 (1H, m), 4.43 (1H, d, J = 15.1 Hz), 4.57 (1H, d, J = 15.1 Hz) 6.71 (2H, d, J = 8.3 Hz); 7.05 (2H, d, J = 8.3 Hz); 9.01 (1H, br, s).

 Reference Example 27. (±) -3-isobutyl-3,4-diazabicyclo / 4.1.0/heptane-2,5-dione.

 To 40 ml of ethyl alcohol, 2.03 g (11.28 mmol) of (±) -3-methyl-2-propen-1-yl / -3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione are added obtained in comparative example 23 and 230 mg of 5% (w / w) of a palladium-carbon catalyst for carrying out catalytic reduction at normal pressure. After completion of the reaction, the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate / hexane to obtain 1.6 g (80%) of the title compound.

Melting point: 150 - 152 ^o C.

NMR (CDCl ₃ , TMS) δ (ppm): 0.91 (3H, d, J = 6.4 Hz), 0.95 (3H, d, J = 6.8 Hz), 1.17 (1H, m), 1.71 (1H, m), 2.05 (1H, m), 2.13 (1H, m), 2.25 (1H, m), 3.23 (1H, dd, J = 6.8 Hz, 14.2 Hz), 3.68 (1H, dd, J = 7.8, 14.2 Hz), 10.14 (1H, br, s).

 Reference Example 28. (±) -3,4-diazabicyclo [4.1.0] -heptane-2,5-dione.

 20.0 g (92.5 mmol) of (±) -3-benzyl-3,4-diazabicyclo / 4.1.0 / -heptane-2,5-dione obtained in comparative example 1 are dissolved in 1 l of methyl alcohol, and 29.2 g (462 mmol) of ammonium formate and 29.2 g (10%) (w / w) of a palladium-carbon catalyst were added to the mixture, followed by heating under reflux for 2 hours. The catalyst was removed by filtration and the solvent was removed by distillation under reduced pressure to yield 12.33 g (100%) of the title compound.

Melting point: 193 - 195 ^o C.

NMR (DMSO-d ₆ , TMS) δ (ppm): 0.99 (1H, m), 1.59 (1H, m), 1.91 (2H, m), 10.05 (2H, br, s).

 Reference Example 29. (±) -2-amino-4-methyl-3,4-diazabicyclo [4.1.0] -heptan-2-en-5-one.

13.77 g (97 mmol) of chlorosulfonyl isocyanate is dissolved in 25 ml of benzene and 12.7 g (88 mmol) of cis-methyl, hydrogencyclopropant-1,2-dicarboxylate, which is obtained in a known manner (Journal of Organic Chemistry, Vol. 36, pp. 3356-3361 (1971)). The mixture was stirred in an oil bath at 60 ^° C. for 30 minutes. After cooling, 13.6 ml (176 mmol) of DMF was added to the mixture, followed by stirring for 30 minutes. Water was added to the mixture, and the reaction mixture was extracted with benzene. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 6.14 g (55.7%) of methyl cis-2-cyancyclopropanecarboxylate.

Boiling point: 94 - 98 ^o C (4 mm Hg column).

NMR (CDCl ₃ , TMS) δ (ppm): 1.43 (1H, m), 1.69 (1H, m), 1.86 (1H, m), 2.15 (1H, m) 3.80 (3H, s).

 2.2 g (96 mmol) of sodium are dissolved in 150 ml of methyl alcohol, and a solution of 6.01 g (48 mmol) of the above compound in 5 ml of methyl alcohol and a solution of 2.21 g (48 mmol) of methylhydrazine in 5 ml are added to the solution. methyl alcohol, followed by stirring at room temperature for 67 hours. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by chromatography on a silica gel column. Recrystallization from ethyl alcohol gives 557 mg (8.6%) of the title compound.

Melting point: 197 - 200 ^o C.

NMR (CDCl ₃ , TMS) δ (ppm): 0.84 (1H, m), 1.54 (1H, m), 1.97 (1H, m), 2.17 (1H, m) 3.18 (3H, s); 4.18 (2H, br, s).

Reference Example 30. 3,4-Dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6,7-dicarboxyimide
1) Dimethyl-3,4-dihydro-2,2-dimethyl-4-oxo-2H-1-benzopyran-6,7-dicarboxylate:
4.2 g of dimethyl 4-acetyl-5-hydroxyphthalate obtained in accordance with the method described in Bulletin of the Chemical Society of Japan, Vol. 57, p. 3221 (1984). 1.0 ml of pyrrolidine and a small amount of molecular sieves (3A) were added to the solution, followed by stirring at room temperature for 3 days. Any insoluble compound was removed by filtration, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.6 g (86.3%) of a yellow oily substance.

NMR (CDCl ₃ , TMS) δ (ppm): 1.48 (6H, s), 2.77 (2H, s), 3.88 (3H, s), 3.93 (3H, s) 7.09 (1H, s), 8.41 (1H, s).

2) Dimethyl-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-benzopyran-6,7-dicarbosilate:
0.15 g (0.51 mmol) of the compound obtained above in (1) is dissolved in 4 ml of methyl alcohol, and 23 mg of sodium borohydride is added to the solution under ice-cooling, followed by stirring at the same temperature for 10 minutes. The reaction mixture was poured into water, slightly acidified with dilute hydrochloric acid, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 0.141 g (93.8%) of a pale yellow oily substance.

NMR (CDCl ₃ , TMS) δ (ppm): 1.30 (3H, s), 1.45 (2H, s), 1.86 (1H, dd, J = 9.5, 13.4 Hz), 2.19 (1H, dd, J = 6.4, 13.4 Hz), 3.85 (3H, s), 3.88 (3H, s), 4.83 (1H, dd, J = 6.4, 9.5 Hz), 6.96 (1H, s), 7.99 (1H, s).

3) Dimethyl-2,2-dimethyl-2H-benzopyran-6,7-dicarbosilate:
0.14 g (0.475 mmol) of the compound obtained above in (2) is dissolved in 5 ml of benzene, and 10 mg of p-toluenesulfonic acid is added to the solution, followed by heating under reflux for 1 hour. After allowing the reaction mixture was cooled, ethyl acetate was added thereto, and the reaction mixture was washed successively with a saturated sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain 0.123 g (93.5%) of a pale yellow oily substance.

NMR (CDCl ₃ , TMS) δ (ppm): 1.44 (6H, s), 3.85 (3H, s), 3.88 (3H, s), 5.71 (1H, d, J = 9.8 Hz), 6.32 (1H, d, J = 9.8 Hz), 6.96 (1H, s), 7.45 (1H, s).

4) 2,2-Dimethyl-2H-1-benzopyran-6,7-dicarboxylic acid anhydride:
2.0 g (7.2 mmol) of the compound obtained in (3) above are dissolved in 10 ml of ethyl alcohol, and 10 ml (20 mmol) and a 2 N aqueous solution of sodium hydroxide are added to the solution, followed by stirring at room temperature in for 1.5 hours. Ethyl alcohol was removed by distillation under reduced pressure, and the residue was acidified with 50 ml of 10% (w / w) hydrochloric acid and extracted with diethyl ether. The diethyl ether layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 2.2 g of a brown oily substance, which was then dissolved in 10 ml of acetic anhydride and the solution was heated under reflux for 7.5 h. Then, the reaction mixture was allowed to cool remove the solvent by distillation under reduced pressure to obtain 1.62 g (79.4%) of a yellow solid.

NMR (CDCl ₃ , TMS) δ (ppm): 1.51 (6H, s), 5.90 (1H, d, J = 10.2 Hz), 6.43 (1H, d, J = 10.2 Hz), 7.26 (1H, s), 7.54 (1H, s).

5) 2,2-dimethyl-2H-1-benzopyran-6,7-dicarboxyimide:
To a solution of 0.50 g (2.17 mmol) of the compound obtained in (4) above in 10 ml of dioxane, 5 ml of concentrated aqueous ammonia solution was added, followed by heating under reflux for 7.5 hours. Then, the reaction the mixture was allowed to cool, the solvent was removed by distillation, and the residue was purified by silica gel column chromatography to obtain 0.23 g (46%) of white crystals.

Melting point: 201-202 ^o C.

NMR (CDCl ₃ , TMS) δ (ppm): 1.48 (6H, s), 5.79 (1H, d, J = 9.9 Hz), 6.40 (1H, d, J = 9.9 Hz), 7.17 (1H, s), 7.43 (1H, s).

6) 3,4-trans-3-bromo-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-benzopyran-6,7-dicarboxiimide:
In a mixed solvent, 3 ml of dimethyl sulfoxide and 0.1 ml of water are dissolved in 99.6 mg (0.43 mmol) of the compound obtained in (5) above, and 150 mg (0.84 mmol) of N-bromosuccinimide are added to the solution, followed by stirring at room temperature for 4 days. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and then with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was washed with chloroform and filtered to obtain 0.114 g (80.5%) of white crystals.

Melting point: 230-232 ^o C.

NMR (DMCO-d ₆ , TMS) δ (ppm): 1.42 (3H, s), 1.58 (3H, s), 4.34 (1H, d, J = 8.3 Hz) 4.88 (1H, dd, J = 8.3, 6.8 Hz), 6.50 (1H, d, J = 6.8 Hz), 7.13 (1H, s), 7.83 ( 1H, s).

7) 3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6,7-dicarboxyimide;
1.02 g (3.13 mmol) of the compound obtained above in (6) is dissolved in 20 ml of DMF, and 0.27 g (6.75 mmol) of 60% (w / w) (oil) is added to the mixture. sodium hydride, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into a mixture of a saturated aqueous solution of ammonium chloride in ethyl acetate, followed by stirring. The organic layer was extracted with ethyl acetate. The combined organic extracts were dried, the solvent was removed by distillation under reduced pressure, and the residue was washed with hexane to obtain 0.62 g (80.8%) of the title compound.

NMR (CDCl ₃ , TMS) δ (ppm): 1.32 (3H, s), 1.63 (2H, s), 3.59 (1H, d, J = 4.4 Hz), 4 02 (1H, d, J = 4.4 Hz), 7.24 (1H, s), 7.86 (1H, s).

где R², R³, R⁴, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, A n и X представляют значения, как они определены выше.The compound obtained in each of examples 1 to 19, described below, represents a racemic compound (Ip) shown below, where the configuration at the positions 3-, 4-, 1'- and 6'- represents S, R, S and R respectively, their organic antipodes or racemate constituting the compound shown below, where the configuration at the 3-, 4-, 1 'and 6'- positions represents S, R, R and S, respectively, and their optical antipodes. The compounds obtained in each of Examples 21-57 described below represent an optically active compound (Ip), wherein the configuration at the 3-, 4-, 1′- and 6 ′ positions is S, R, S and R, respectively, or S , R, R and S, respectively

where R ² , R ³ , R ⁴ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , A n and X represent the values as defined above.

Example 1. 3.4-trans-4- / 3-benzyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / 3,4-dihydro-2,2-dimethyl- 3-hydroxy-2H-1-benzopyran-6-carbonitrile
3.0 g (13.8 mmol) of (±) -3-benzyl-3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione obtained in Reference Example 1, 2 are added to 100 ml of ethyl alcohol. 79 g (13.8 mmol) (±) -3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6-carbonitrile and 1.1 ml (13.8 mmol) pyridine and the mixture was heated under reflux for 16 hours. The solvent was removed by distillation under reduced pressure and ethanol was added to the residue. Recrystallization of insoluble crude crystals from methyl alcohol afforded 1.41 g (24.3%) of the title compound.

Melting point 242-245 ^o C (decomposition).

The value of R _f = 0.50 (thin-layer chromatography on silica gel (TLS), the solvent for the manifestation: chloroform / methyl alcohol = 20: 1 (volume / volume).

NMR (CDCl ₃ , TMS) δ (ppm): 1.01 (1H, s), 1.25 (3H, s), 1.44 (3H, s), 1.73 (1H, m) , 2.18 (1H, m), 2.33 (1H, m), 3.00 (1H, d, J = 4.3 Hz), 3.76 (1H, dd, J = 4.3, 7 , 3 Hz), 4.75 (1H, d, J = 14.4 Hz), 4.85 (1H, d, J = 14.4 Hz), 5.60 (1H, d, J = 7.8 Hz), 6.88 (1H, d, J = 8.3 Hz), 7.30 (5H, m), 7.48 (1H, dd, J = 2.0, 8.3 Hz), 7, 52 (1H, s).

Examples 2-8. The compounds shown in the table. 2 below, obtained in the same manner as in example 1. Melting points (mp.), R _f value according to TLC on silica gel and NMR data of the compounds are also shown in table. 2. NMR spectra were recorded with CDCl ₃ , except as noted. In the table. 2 EtOAc is ethyl acetate and MeOH is methyl alcohol (hereinafter the same).

 Example 9. 3,4-trans-3,4-dihydro-2,2-dimethyl-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5- yloxy / 6-trifluoromethoxy-2H-1-benzopyran-3-ol.

 In 20 ml of ethyl alcohol, 1.0 g (3.84 mmol) of (±) -3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-trifluoromethoxy-2H-1-benzopyran, which was obtained according to the method of JP-B-1-151571 (the term “JP-B”, as used here, means “passed Japanese published application”) and 0.6 g (728 mmol) (±) -3- are added to the solution methyl 3,4-diazabicyclo (4.1.0) heptane-2,5-dione and 0.35 ml (4.34 mmol) of pyridine. The mixture was heated under reflux for 16 hours. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate / hexane to obtain 0.32 g (20.6%) of the title compound.

Melting point: 189-190 ^o C.

The value of R _f : 0.33 (CHCl ₃ ) MeOH = 20: 1 vol./about.

NMR (CDCl ₃ , TMS) δ (ppm): 0.99 (1H, m), 1.32 (3H, s), 1.51 (3H, s), 1.68 (1H, m) , 2.15-2.30 (2H, m), 3.25 (3H, s), 3.90-3.96 (2H, m), 5.71 (1H, d, J = 7.3 Hz ), 6.85 (1H, d, J = 9.3 Hz), 7.10 (1H, d, J = 9.3 Hz), 7.15 (1H, s).

 Example 10. 3,4-trans-3,4-dihydro-2,2-dimethyl-4- / 3-methyl-2-oxo-3,4-diazabicyclo /4.1.0/hept-4-en-5- yloxy / -6-phenylsulfonyl-2H-1-benzopyran-3-ol.

 0.96 g (3.03 mmol) of (±) -3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-phenylsulfonyl-2H-1-benzopyran, which was prepared, are suspended in 15 ml of ethyl alcohol. according to method JP-B-1-287083 and 0.81 g (5.78 mmol) of (±) -3-methyl-3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione and 0 is added to the suspension 3 ml (3.9 mmol) of pyridine. The mixture was heated at reflux for 6 hours. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography. Recrystallization from ethyl acetate / hexane gave 0.181 g (13%) of the title compound.

Melting point: 118-121 ^o C.

The value of R _f : 0.24 (CHCl ₃ ) MeOH = 20: 1 v / v.

NMR (CDCl ₃ , TMS) δ (ppm): 0.99 (1H, m), 1.32 (3H, s), 1.51 (3H, s), 1.66-1.72 ( 1H, m), 2.14-2.26 (2H, m), 3.23 (3H, s), 3.92 (1H, dd, J = 3.4, 7.3 Hz) 4.23 ( 1H, br, s), 5.76 (1H, d, J = 7.3 Hz), 6.91 (1H, d, J = 8.8 Hz), 7.48-7.58 (3H, m ), 7.74 (1H, dd, J = 2.4, 8.8 Hz), 7.88-7.94 (3H, m).

 Example 11. 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4- en-5-yloxy / -2H-1-benzopyran-6-sulfonamide.

 To 20 ml of DMF was added 2.5 g (7.44 mmol) of trans-3-bromo-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-benzylpyran-6-sulfonamide, which was prepared according to method JP-B-2-300182 and 0.75 g (18.75 mmol) of 60% (w / w) sodium hydride are added to the mixture, followed by stirring at room temperature for 20 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and adjusted to pH 5 with hydrochloric acid. The reaction mixture was extracted with ethyl acetate, the extract was washed with a saturated solution of ammonium chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 2.6 g of a pale brown oily substance. The oily substance is dissolved in 40 ml of ethyl alcohol and 1.05 g (7.50 mmol) of (±) -3-methyl-3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione and 1.0 ml are added (12.3 mmol) of pyridine to the mixture, followed by heating under reflux for 15 hours. The solvent was removed by distillation under reduced pressure and the residue was purified by chromatography on a silica gel column, and recrystallization from chloroform gave 0.262 g (8.9%) specified in the name of the compound.

Melting point: 236-238 ^o C.

The value of R _f : 0,40 (CHCl ₃ ) MeOH = 10: 1 v / v.

NMR (DMSO-d ₆ , TMS) δ (ppm): 0.86 - 0.92 (1H, m), 1.27 (3H, s), 1.40 (3H, s), 1, 62 - 1.67 (1H, m), 2.15 - 2.24 (2H, m), 3.13 (3H, s), 3.78 (1H, dd, J = 5.4, 6.4 Hz), 5.73 (1H, d, J = 5.4 Hz), 5.88 (1H, d, J = 5.4 Hz), 6.95 (1H, d, J = 8.3 Hz) 6.65 (1H, dd, J = 8.3, 2.0 Hz); 7.72 (1H, d, J = 2.0 Hz).

 Example 12. 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4/3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4- en-5-yloxy-7-nitro-2H-1-benzopyran-6-acetamide.

 To 20 ml of ethanol 556 mg (2.0 mmol) of (±) -3,4-dihydro-2,2-dimethyl-3,4-epoxy-7-nitro-2H-1-benzopyran-6-acetamide are added, which is obtained according to the method of JP-B-59-1475, 280 mg (2.0 mmol) (±) -3-methyl-3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione and 0.16 ml (2.0 mmol) of pyridine and the mixture was heated under reflux for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography, followed by recrystallization from ethyl acetate, to give 123 mg (14.8%) of the indicated in the name of the compound.

Melting point: 239 - 240 ^o C.

R _f value: 0.34 (CHCl ₃ ) MeOH = 20: 1 v / v.

NMR (CDCl ₃ , TMS) δ (ppm): 1.17 (1H, m), 1.32 (3H, s), 1.56 (3H, s), 1.70 (1H, m) , 2.21 (2H, m), 2.25 (3H, s), 3.25 (3H, s), 3.75 (1H, d, J = 3.4 Hz), 3.96 (1H, dd, J = 3.4, 7.8 Hz), 5.79 (1H, d, J = 7.8 Hz), 7.68 (1H, s), 8.76 (1H, s), 10, 00 (1H, br, s).

 Example 13. 3,4-trans-3,4-dihydro-2,2-dimethyl-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5- yloxy / -7-nitro-2H-1-benzopyran-3-ol.

 To 20 ml of ethyl alcohol was added 442 mg (2.0 mmol) of (±) -3,4-dihydro-2,2-dimethyl-3,4-epoxy-7-nitro-2H-1-benzopyran, which was obtained according to the method J. Med. Chem., Vol. 26 p. 1582 - 1589 (1983), 280 mg (2.0 mmol) (±) -3-methyl-3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione and 0.16 ml (2.0 mmol) ) pyridine and the mixture was heated under reflux for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from ethyl alcohol to obtain 127 mg (17.5%) of the title compound.

Melting point: 236 - 237 ^o C.

The value of R _f : 0.29 (ethyl acetate).

NMR (CDCl ₃ , TMS) δ (ppm): 1.00 (1H, m), 1.34 (3H, s), 1.54 (3H, s), 1.69 (1H, m) , 2.21 (1H, m), 2.28 (1H, m), 3.25 (3H, s), 3.84 (1H, d), J = 3.4 Hz), 3.97 (1H dd, J = 3.4 7.3 Hz), 5.78 (1H, d, J = 7.3 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.71 ( 1H, d, J = 2.0 Hz), 7.78 (1H, dd, J = 2.0, 8.3 Hz).

 Example 14. 3,4-trans-3,4-dihydro-3-hydroxy-4- / 3-methyl-2-oxo-3,4-diazabicyclo (4.1.0) hept-4-en-5-yloxy / -2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile.

 To 10 ml of ethyl alcohol, 266 (1.23 mmol) of (±) -3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile, which was prepared according to the known method (J. Med. Chem., Vol. 34, pp. 3074-3085 (1991)), 133 mg (1.23 mmol) (±) -3-methyl-3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione and 0.1 ml (0.13 mmol) of pyridine and the mixture is heated at the boil under reflux for 7 days. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography. Recrystallization from ethyl acetate gave 125 mg (28.4%) of the title compound.

Melting point 226 - 227 ^o C.

The value of R _f : 50,21 (ethyl acetate).

NMR (CDCl ₃ , TMS) δ (ppm): 1.03 (1H, m), 1.24 (3H, s), 1.42 (3H, s), 1.50 (3H, s) 1.73 (1H, m), 2.22 - 2.31 (2H, m), 3.24 (3H, s), 3.95 (1H, s), 5.83 (1H, s), 6.90 (1H, d, J = 8.3 Hz), 7.51 (1H, dd, J = 2.0, 8.3 Hz), 7.65 (1H, d, J = 2.0 Hz )

 Example 15. 3,4-trans-3,4-dihydro-3-hydroxy-4- / 3-methyl-2-oxo-3,4-diazabicyclo (4.1.0) hept-4-en-5-yloxy / -2,2-tetramethylene-2H-1-benzopyran-6-carbonitrile 1/2 hydrate.

 The title compound was prepared in the same manner as in Example 1, except that (±) -3,4-dihydro-3,4-epoxy-2,2-tetramethylene-2H-1-benzopyran-6- was used. carbonitrile obtained according to method JP-B-294677.

Melting point: 207 - 210 ^o C.

The value of R _f : 0.30 (CHCl ₃ ) MeOH = 20: 1 v / v.

NMR (CDCl ₃ , TMS) δ: 0.99 - 1.03 (1H, m), 1.64 - 1.98 (8H, m), 2.08 - 2.28 (3H, m), 3, 24 (3H, s), 3.87 (1H, d, J = 3.9 Hz), 4.13 (1H, dd, J = 3.9, 6.8 Hz), 5.73 (1H, d , J = 6.8 Hz), 6.91 (1H, d, J = 8.3 Hz), 7.50 (1H, dd, J = 8.3, 2.0 Hz) 7.62 (1H, d, J = 2.0 Hz).

 Example 16. 3,4-trans-3,4-dihydro-2,2-dimethyl-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5- yloxy / 2H-pyrano / 3,2-s / pyridin-3-ol.

 The title compound was prepared in the same manner as in Example 1, except that (±) -3,3-dihydro-2,2-dimethyl-3,4-epoxy-2H-pyrano / 3,2- was used. s / pyridine obtained according to the method of JP-B-61-293984 instead of (±) -3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6-carbonitrile.

The value of R _f : 0.46 (CHCl ₃ ) MeOH = 10: 1 v / v.

NMR (CDCl ₃ , TMS) δ: 0.97 - 1.01 (1H, m), 1.32 (3H, s), 1.54 (3H, s), 1.67 - 1.73 (1H, m), 2.24 - 2.37 (2H, m), 3.26 (3H, s), 3.93 (1H, dd, J = 2.0, 7.8 Hz), 4.82 (1H d, J = 2.0 Hz), 5.66 (1H, d, J = 7.8 Hz), 6.77 (1H, d, J = 5.4 Hz), 8.36 (1H, d , J = 5.4 Hz), 8.50 (1H, s).

 Example 17. 3,4-trans-4- / 3- / 2-aminoethyl / -2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -3,4-dihydro -2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile.

 303 mg (0.8 mmol) of 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 3- / 2-hydroxyethyl-2-oxo-3 are added to 10 ml of THF , 4-diazabicyclo (4.1.0) hept-4-en-5-yloxy / -2H-1-benzopyran-5-carbonitrile obtained in Example 6, 456 mg (1.6 mmol) of dibenzylimidodicarboxylate and 419 mg (1, 6 mmol) of triphenylfoefin and a solution of 278 mg (1.6 mmol) of diethyl azodicarboxylate in 2 ml of THF are added dropwise to the mixture. The mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate / hexane to obtain 312 mg (61.1%) of 3,4-trans-4- / 3- / 2-N, N-bis / benzyloxycarbonyl / aminoethyl / -2 -oxo-3,4-diazabicyclo (4.1.0) hept-4-en-5-yloxy / -3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-4-carbonitrile.

Melting point: 148 - 149 ^o C.

NMR (CDCl ₃ , TMS) δ (ppm): 0.91 (1H, m), 1.37 (3H, s), 1.47 (3H, s), 1.54 (1H, m) , 1.91 (2H, m), 3.46 (1H, m), 3.79 (1H, dd, J = 6.4, 6.8 Hz), 3.85 (1H, d, J = 6 , 8 Hz), 3.91 (1H, m), 4.14 (1H, m), 4.26 (1H, m), 5.18 (2H, d, J = 12.2 Hz), 5, 25 (2H, d, J = 12.2 Hz), 5.71 (1H, d, J = 6.4 Hz), 6.90 (1H, d, J = 8.8 Hz), 7.26 ( 10H, m), 7.44 (1H, d, J = 2.0 Hz), 7.49 (1H, dd, J = 2.0, 8.8 Hz).

 291 mg (0.455 mmol) of the compound obtained above are dissolved in 20 ml of methyl alcohol, and 30 mg (10% (w / w) of palladium-carbon catalyst is added to the mixture for hydrogenolysis at normal pressure. After completion of the reaction, the catalyst is removed by filtration and the solvent was removed by distillation under reduced pressure to obtain 168 mg (100%) of the title compound.

The value of R _f : 0,15 (CHCl ₃ ) MeOH = 4: 1, vol./about.

NMR (CDCl ₃ , TMS) δ (ppm): 1.03 (1H, m), 1.32 (3H, s), 1.50 (3H, s), 1.73 (1H, m) , 1.60 - 2.70 (3H), 2.21 (1H, m), 2.30 (1H, m), 3.00 (2H, m), 3.54 (1H, m), 3, 88 (1H, d, J = 7.3 Hz), 3.89 (1H, m), 5.82 (1H, d, J = 7.3 Hz), 6.90 (1H, d, J = 8 8 Hz), 7.50 (1H, dd, J = 2.0, 8.8 Hz), 7.63 (1H, d, J = 2.0 Hz).

 Example 18. 3,4-trans-4- / 3- / 2-acetamidoethyl / -2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -3,4-dihydro -2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile.

 108 mg (0.29 mmol) of 3,4-trans-4- / 3- / 2-aminoethyl / -2-oxo-3,4-diazabicyclo / 4.1.0 / hept-5-ene are added to 10 ml of methylene chloride. 5-yloxy / -3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile obtained in Example 17 and 0.04 ml (0.29 mmol) of triethylamine and the mixture is added dropwise a solution of 23 mg (0.29 mmol) of acetyl chloride in 2 ml of methylene chloride, followed by stirring at room temperature for 2 hours. The solvent is removed by distillation under reduced pressure, followed by purification by chromatography on a column of silica gel and recrystallization and ethyl acetate that to obtain 55 mg (45.8%) of the title compound.

Melting point: 230 - 231 ^o C.

The value of R _f : 0,58 (CHCl ₃ ) MeOH = 5: 1, vol./about.

NMR (CDCl ₃ , TMS) δ (ppm): 1.08 (1H, m), 1.37 (3H, s), 1.54 (3H, s), 1.73 (1H, m) , 1.95 (3H, s), 2.25 (2H, m), 3.09 (1H, m), 3.22 (1H, m), 3.85 (1H, dd, J = 7.3 , 7.8 Hz), 4.13 (1H, m), 4.32 (1H, m), 4.64 (1H, d, J = 7.3 Hz), 5.75 (1H, br, s ), 6.06 (1H, d, J = 7.8 Hz), 6.89 (1H, d, J = 8.3 Hz), 7.48 (1H, dd, J = 2.0, 8, 3 Hz), 7.56 (1H, d, J = 2.0 Hz).

 Example 19. 3,4-trans-3,4-dihydro-2,2-dimethyl-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5- yloxy / -6-pentafluoroethyl-2H-1-benzopyran-3-ol.

 To 1.5 L of diethyl ether, 12.63 g (33.67 mmol) of 3-bromo-3,4-dihydro-2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran-4-ol obtained according to by JP-B-2-237985, and 30.2 g of potassium hydroxide were added to the mixture, followed by stirring at room temperature for 54 hours. The insoluble compound was removed by filtration and the solvent was removed by distillation under reduced pressure, in 9.5 g (96) , 2%) 3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-pentafluoroethyl-2H-1-benzopyran.

NMR (CDCl ₃ , TMS) δ (ppm): 1.30 (3H, s), 1.60 (3H, s), 3.54 (1H, d, J = 4.4 Hz), 3 94 (1H, d, J = 4.4 Hz), 6.90 (1H, d, J = 8.3 Hz), 7.46 (1H, dd, J = 2.0, 8.3 Hz) 7.57 (1H, d, J = 2.0 Hz).

 2.50 g (8.50 mmol) of the compound obtained above, 1.20 g (8.56 mmol) (±) -3-methyl-3,4-diazabicyclo / 4.1.0 / heptane are added to 100 ml of ethyl alcohol. -2,5-dione and 0.672 g (8.50 mmol) of pyridine, and the mixture was heated under reflux for 20 hours. The solvent was removed by distillation under reduced pressure. Purify the residue by chromatography on a silica gel column to obtain 1.22 g (33.0%) of the title compound.

Melting point: 190 - 191 ^o C.

The value of R _f : 0,31 (ethyl acetate).

NMR (CDCl ₃ , TMS) δ (ppm): 0.99 (1H, m), 1.35 (3H, s), 1.53 (3H, s), 1.69 (1H, m) , 2.17 - 2.30 (2H, m), 3.25 (3H, s), 3.79 (1H, d, J = 3.4 Hz), 3.96 (1H, dd, J = 3 4, 7.3 Hz), 5.75 (1H, d, J = 7.3 Hz), 6.95 (1H, d, J = 8.8 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.53 (1H, s).

 Example 20. 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy- / 4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4 en-5-yloxy / -2H-1-benzopyran-6,7-dicarboxyimide.

 The compound obtained above is identified as a racemate consisting of compound (1q) shown below, where the configurations at the 3-, 4-, 1'-, and 6 'positions represent S, R, S, and R, respectively, and their optical antipodes or racemate consisting of compound (1q), where the configuration at the positions indicated above represents S, R, R and S, respectively, and their optical antipodes.

В 20 мл ДМФА растворяют 0,76 г (3,10 ммоль) 3,4-дигидро-2,2-диметил-3,4-эпокси-2H-1-бензопиран-6,7- дикарбоксиимида, полученного в сравнительном примере 30, и 0,44 г (3,14 ммоль) (±)-3-метил-3,4-диазабицикло/4.1.0/гептан-2,5-диона и к раствору добавляют 0,6 мл (7,43 ммоль) пиридина. Смесь перемешивают при 90^oC в течение 38 ч. Реакционную смесь концентрируют при пониженном давлении и к смеси добавляют этилацетат и воду, с последующим перемешиванием. Органический слой отделяют, а водный слой далее экстрагируют этилацетатом. Органические слои объединяют и сушат. Растворитель удаляют при пониженном давлении и остаток чистят хроматографически на колонке с силикагелем и перекристаллизовывают из смешанного растворителя метиловый спирт и изопропиловый эфир до получения 62 мг указанного в названии соединения.

0.76 g (3.10 mmol) of 3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6,7-dicarboxyimide obtained in comparative example 30 was dissolved in 20 ml of DMF. and 0.44 g (3.14 mmol) of (±) -3-methyl-3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione and 0.6 ml (7.43 mmol) is added to the solution ) pyridine. The mixture was stirred at 90 ^° C. for 38 hours. The reaction mixture was concentrated under reduced pressure and ethyl acetate and water were added to the mixture, followed by stirring. The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The organic layers are combined and dried. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography and methyl alcohol and isopropyl ether were recrystallized from a mixed solvent to obtain 62 mg of the title compound.

Melting point: 250 - 253 ^o C.

The value of R _f : 0,40 (CHCl ₃ ) MeOH = 20: 1 v / v.

NMR (DMSO-d ₆ , TMS) δ (ppm): 0.8 - 1.1 (1H, m), 1.30 (3H, s), 1.43 (3H, s), 1, 5 - 1.9 (1H, m), 2.0 - 2.4 (2H, m), 3.14 (3H, s), 3.85 (1H, t, J = 5.4 Hz), 5 77 (1H, d, J = 7.0 Hz), 5.98 (1H, d, J = 5.3 Hz), 7.16 (1H, s), 7.65 (1H, s), 11 23 (1H, s).

 Example 21. / 3S, 4R, 1'S, 6'R / -4- / 3-benzyl-2-oxo-3,4-diazabicyclo /4.1.0/hept-4en-5-yloxy/-3,4 -dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile.

 To 20 ml of ethyl alcohol, 800 mg (±) -3-benzyl-3,4-diazabicyclo / 4.1.0 / heptane-2,5-dione obtained in Reference Example 1, 774 mg (3 , 7 mmol) - (-) - / 3S, 4S / -3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6-carbonitrile and 0.4 ml of pyridine and a mixture heated at reflux for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from isopropyl ether to obtain 490 mg (31.7%) of the title compound.

 X-ray diffraction data confirm the S and R configuration at positions 1'- and 6'-, respectively.

Melting point: 118 - 120 ^o C.

The value of R _f : 0.50 (CHCl ₃ ) MeOH = 20: 1 v / v.

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : -212.8 ^° (c = 1, MeOH).

NMR (CDCl ₃ , TMS) δ (ppm): 1.01 (1H, m), 1.25 (3H, s), 1.44 (3H, s), 1.73 (1H, m) , 2.18 (1H, m), 2.33 (1H, m), 3.00 (1H, d, J = 4.3 Hz), 3.76 (1H, dd, J = 4.3, 7 , 3 Hz), 4.75 (1H, d, J = 14.4 Hz), 4.85 (1H, d, J = 14.4 Hz), 5.60 (1H, d, J = 7.8 Hz), 6.88 (1H, d, J = 8.3 Hz), 7.30 (5H, m), 7.48 (1H, dd, J = 2.0, 8.3 Hz), 7, 52 (1H, s).

Examples 22-46. The compounds shown in the table. 3, obtained in the same manner as in example 21. Also shown are the melting points (mp), the value of R _f according to thin-layer chromatography on silica gel, specific rotation and NMR data obtained in CDCl ₃ , except as noted. The specific rotation was measured at 25 ^o C, except as noted.

Example 47. / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / 2H-1-benzopyran-6-carbonitrile.

Method A:
To 500 ml of ethanol was added 12.33 g (97 mmol) of (±) -3,4-diazabicyclo- / 4.1.0 / heptane-2,5-dione obtained in Reference Example 28, 18.6 g (92.5 mmol) / 3S, 4S / -3,4-dihydro-2,2-dimethyl-3,4-ethoxy-2H-1-benzopyran-6-carbonitrile and 7.5 ml (92.5 mmol) of pyridine, followed by refluxing for 14 hours. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography and high performance liquid chromatography to obtain 2.4 g (7.9%) of the title compound.

The value of R _f : 0.29 (ethyl acetate).

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : -168.1 ^° (c = 1, MeOH).

NMR (CDCl ₃ , TMC) δ (ppm): 1.18 (1H, m), 1.33 (3H, s), 1.52 (3H, s), 1.60-2.10 ( 1H, br, s), 1.81 (1H, m), 2.21 (2H, m), 3.92 (1H, d, J = 7.3 Hz), 5.71 (1H, d, J = 7.3), 6.91 (1H, d, J = 8.3 Hz), 7.50 (1H, dd, J = 2.0, 8.3 Hz), 7.59 (1H, d, J = 2.0 Hz), 7.71 (1H, s).

Method B:
5.91 g (13.2 mmol) (3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4 are added to 450 ml of 1,2-dichloroethane - / 3- / 4-methoxybenzyl / -2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-En-5-yloxy / -2H-1-benzopyran-6-carbonitrile obtained in Example 40, and 17.7 g (78 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and 0.9 ml (50 mmol) of water was added to the mixture, followed by heating under reflux for 8 h. Insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure. Chromatography on a silica gel column gave 2.81 g (65.1%) of the indicated wow in the name of the compound.

Example 48. / 3S, 4R, 1'R ^* , 6'S ^* / -4- / 3-cyanomethyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / -3 , 4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile.

200 mg (0.61 mmol) / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 2-oxo- are added to 3 ml of acetone. 3,4-diazabicyclo (4.1.0) hept-4-en-5-yloxy / -2H-1-benzopyran-6-carbonitrile obtained in Example 47 and 85 mg (0.61 mmol) of potassium carbonate, followed by stirring . A solution of 147 mg (1.22 mmol) of bromoacetonitrile in 2 ml of acetonitrile was added to the mixture, followed by heating under reflux for 4 hours. 585 mg (4.88 mmol) of bromoacetonitrile and 170 mg (1.22) were then added to the mixture. mmol) of potassium carbonate, followed by heating under reflux for 3 hours. Insoluble matter was removed by filtration and the solvent was removed by distillation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 81 mg (36.3%) of the title compound.

The value of R _f : 0.47 (ethyl acetate).

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : -168.4 ^° (c = 1, MeOH).

NMR (CDCl ₃ , TMC) δ (ppm): 1.18 (1H, m), 1.39 (3H, s), 1.50 (3H, s), 1.82 (1H, m) 2.26 (1H, m), 2.34 (1H, m), 2.82 (1H, d, J = 5.4 Hz), 3.97 (1H, dd, J = 5.4, 6 , 9 Hz), 4.36 (1H, d, J = 17.1 Hz), 4.79 (1H, d, J = 17.1 Hz), 5.82 (1H, d, J = 6.9 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.52 (1H, dd, J = 2.0, 8.8 Hz), 7.60 (1H, d, J = 2 , 0 Hz).

Examples 49-52. The compounds shown in the table. 4 were obtained in the same manner as in Example 48. Melting temperature data (mp), R _f value according to thin-layer chromatography on silica gel, specific rotation and NMR data of the compounds are also shown. NMR spectra were recorded in CDCl ₃ , except as noted. Specific rotation was measured at 25 ^o C except as noted.

Example 53. / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-2,2-dimethyl-3-hydroxy-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-ylamino / -2H-1-benzopyran-6-carbonitrile.

 557 mg (4.0 mmol) of (±) -2-amino-4-methyl-3,4-diazabicyclo / 4.1.0 / hept-2-en-5-one obtained in Reference Example 29 was dissolved in 25 ml of dimethyl sulfoxide. and 160 mg (4 mmol) of 60% sodium hydride and 885 mg (4.4 mmol) / 3S, 4S / -3,4-dihydro-2,2-dimethyl-3,4-epoxy-4H- are added to the solution 1-benzopyran-6-carbonitrile, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from ethyl acetate to obtain 152 mg (11.1%) of the title compound.

Melting point: 157-158 ^o C.

The value of R _f : 0.24 (CHCl ₃ ) MeOH = 10: 1 v / v.

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : -217.0 ^° (c = 1, MeOH).

NMR (CDCl ₃ , TMC) δ (ppm): 1.00 (1H, m), 1.28 (3H, s), 1.52 (3H, s), 1.66 (1H, m) , 2.00 (1H, m), 2.21 (1H, m), 3.22 (3H, s), 3.73 (1H, dd, J = 2.0, 8.3 Hz), 4, 39 (1H, d, J = 7.8 Hz), 4.82 (1H, d, J = 2.0 Hz), 4.91 (1H, dd, J = 7.8, 8.3 Hz), 6.90 (1H, d, = 8.3 Hz), 7.49 (1H, dd, J = 2.0, 8.3 Hz), 7.67 (1H, br, s).

 Example 54. / 3S, 4R, 1'S, 6'R / -3-acetoxy-4- / 3-benzyl-2-oxo-3,4-diazabicyclo (4.1.0) hept-4-en-5-yloxy / -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile.

 To 10 ml of methylene chloride add 0.31 g (0.74 mmol) /3S.4R.1'S.6'R/-4-/3- benzyl-2- oxo-3,4- diazabicyclo/4.1.0/hept- 4-en-5-yloxy / -3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile obtained in Example 21 and 0.16 ml was added dropwise to the mixture (2 mmol) of pyridine (0.16 ml) (2 mmol) of acetyl chloride, followed by stirring at room temperature for 1 day. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from diisopropyl ether to obtain 0.145 g (42.6%) of the title compound.

Melting point: 149-151 ^o C.

The value of R _f : 0.74 (ethyl acetate).

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : -92.9 ^° (c = 1, MeOH).

NMR (CDCl ₃ , TMS) δ (ppm): 0.94 (1H, m), 1.35 (3H, s), 1.42 (3H, s), 1.64 (1H, m) , 1.99 (3H, s), 2.06 (1H, m), 2.29 (1H, m), 4.62 (1H, d, J = 14.1 Hz), 4.97 (1H, d, J = 14.1 Hz), 5.34 (1H, d, J = 5.9 Hz), 5.74 (1H, d, J = 5.9 Hz), 6.92 (1H, d, J = 8.3 Hz), 7.25-7.35 (5H, m), 7.50 (1H, dd, J = 2.0, 8.3 Hz), 7.52 (1H, d, J = 2.0 Hz).

 Example 55. / 3S, 4R, 1'S, 6'S * / - 3-acetoxy-4- / 3- / 2-chlorobenzyl / -2-oxo-3,4-diazabicyclo / 4.1.0 / -hept-4-ene 5-yloxy / -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile.

The title compound was prepared in the same manner as in Example 54, except that / 3S, 4R, 1'R ^* , 6'S ^* / -4- / 3- / 2-chlorobenzyl-2-oxo-3 was used, 4-diazabicyclo (4.1.0) hept-4-en-5-yloxy / -3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile obtained in example 33, instead of the compound obtained in example 21.

R _f value: 0.64 (CHCl ₃ ) MeOH = 20: 1 v / v.

[α] $\genfrac{}{}{0ex}{}{\text{27}}{\text{D}}$ : -132.0 ^° (c = 1, CHCl ₃ ).

NMR CDCl ₃ , TMS) δ (ppm): 0.99-1.03 (1H, m), 1.32 (3H, s), 1.41 (3H, s), 1.64-1 70 (1H, m), 2.05 (3H, s), 2.07-2.12 (1H, m), 2.29-2.35 (1H, m), 4.67 (1H, d , J = 14.6 Hz), 5.22 (1H, d, J = 14.6 Hz), 5.30 (1H, d, J = 5.4 Hz), 5.71 (1H, d, J = 5.4 Hz), 6.69 (1H, d, J = 8.8 Hz), 7.19-7.35 (5H, m), 7.46 (1H, dd, J = 2.06 8 , 8 Hz).

Example 56. / 3S, 4R, 1'R ^* , 6'S ^* / -3,4-dihydro-3-hydroxy-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 / hept- 4-en-5-yloxy / -2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile.

 300 mg (0.85 mmol) of 3,4-trans-3,4-dihydro-3-hydroxy-4- / 3-methyl-2-oxo-3,4-diazabicyclo / 4.1.0 are dissolved in 15 ml of methyl alcohol (hept-4-en-5-yloxy) -2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile obtained in Example 14 and is divided into enantiomers by high performance liquid chromatography ("CHIR AI PAK AD "; Daicel Chemical Industries, LTD., Ethyl alcohol / hexane = 15:85, v / v). Recrystallization from ethyl acetate (hexane gives 102 mg (34.0%) of the title compound.

Melting point: 192-193 ^o C.

The value of R _f : 0.21 (ethyl acetate).

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : -162.2 ^° (c = 1, ethyl acetate).

NMR (CDCl ₃ , TMC) δ (ppm): 1.04 (1H, m), 1.25 (3H, s), 1.42 (3H, s), 1.50 (3H, s) 1.74 (1H, m), 2.22-2.35 (2H, m), 3.25 (3H, s), 3.90 (1H, s), 5.83 (1H, s), 6.91 (1H, d, J = 8.30 Hz), 7.51 (1H, dd, J = 1.95, 8.30 Hz), 7.66 (1H, s).

Example 57. / 3S, 4R, 1'R ^* , 6'S ^* / -4- / 3- / 2-chlorobenzyl / -2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5- yloxy / 3,4-dihydro-2,2-dimethyl-3-formyloxy-2H-1-benzopyran-6-carbonitrile.

To 15 ml of benzene add 1.5 g (3.3 mmol) / 3S, 4R, 1'R ^* , 6'S ^* / -4- / 3- / 2-chlorobenzyl / -2-oxo-3,4-diazabicyclo / 4.1.0 / hept-4-en-5-yloxy / 3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile obtained in Example 33 and 5 ml (132 , 6 mmol) of formic acid, followed by heating under reflux for 19 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.706 g (44.3%) of the title compound.

The value of R _f : 0,64 (CHCl ₃ ) MeOH = 20: 1 vol./about.

[α] $\genfrac{}{}{0ex}{}{\text{17}}{\text{D}}$ : -100.6 ^° (c = 1, MeOH).

NMR (CDCl ₃ , TMC) δ (ppm): 1.00 - 1.04 (1H, m), 1.33 (3H, s), 1.43 (3H, s), 1.65 - 1.71 (1H, m), 2.08 - 2.13 (1H, m), 2.29 - 2.35 (1H, m), 4.70 (1H, d, J = 15.1 Hz) , 5.18 (1H, d, J = 15.1 Hz), 5.40 (1H, d, J = 6.3 Hz), 5.78 (1H, d, J = 6.3 Hz), 6 89 (1H, d, J = 8.3 Hz), 7.20 - 7.34 (5H, m), 7.47 (1H, d, J = 8.3 Hz), 8.00 (1H, with).

 Test Example 1. Potassium metabolism activity (opening potassium channels).

1) The potassium metabolism activity of the test compounds is shown below in table. 5 was determined according to a known method (Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 338, pp. 319 - 326 (1988)). ⁸⁶ R _b was introduced into the Wistar rat excised aorta segment, and the segment was perfused with a solution containing the test compound for 10 minutes. The potassium metabolism activity of the test compound was expressed as the effective concentration at which the area under the peak of the release rate of ⁸⁶ R _b reached 0.2 ( ^EC AUCO.2).

 The results are shown in table. 5.

 2) Twenty-two-week-old male rats with spontaneous hypertension (rat weight 350-420 g) received intravenous injections of 30 mg / kg glibenclamide (Sigma Chemical Compahy) having antagonistic potassium tubule opening activity, or as a solvent control. After 10 minutes, 0.1 mg / kg of the compound of Example 1 was administered intravenously and a change in blood pressure was observed 6 hours after the injection (Journal of Pharmacology and Experimental Therapeutics, Vol. 248, p. 1261 (1989). The results are shown below in table. 6.

 From these results it is seen that each of the compounds of examples 1, 22, 23, 47 and 56, have activity against the opening of potassium tubules and potassium metabolism.

 Test Example 11. Antihypertensive activity in spontaneous rat hypertension.

 Male rats with spontaneous hypertension (16 to 20 weeks old weighing 300 to 400 g), fed as needed, were vigorously subjected to oral administration of the test compound suspended in a 0.5% (w / v) aqueous solution of carboxymethyl cellulose. Systolic blood pressure was measured 1, 2, 4, 6, 8, 24, 30, or 48 hours after ingestion by tail clamping (Arzneimittel-Forschung, Vol. 18, p. 1285 - 1287 (1968)).

The antihypertensive activity of the test compound was obtained as a dose effective to lower blood pressure by 50 mm Hg. (ED _{50 mmHg).} In addition, the time of the onset of maximum activity and the maximum increase in heart rate at a dose of a decrease in blood pressure of 50-60 mm Hg were measured. The results are shown below in table. 7.

 The statistical difference between the test compound and EMD 57283 was analyzed according to Student t-tests.

 Each of the compounds of examples 21, 24, 32, 33, 36, 37 and 56 shows a high antihypertensive activity, compared with the reference drug, a slower onset of action and a decrease in side effect in increasing the heart rate. In addition, these compounds have continuous activity.

 Test Example 3. Effect on renal blood flow.

 20-week-old male rats with spontaneous hypertension (weight 350 - 430 g) were anesthetized with pentobarbital (30 mg-kg, ext. Abdominal). An incision was made on the left side of the abdominal cavity, and a Doppler probe for measuring blood flow was installed on the left renal artery, and a code probe (wire input) passed under the skin of the back and was removed from the back of the neck. One week after the operation, the code probe contacted the Doppler meter for blood flow and measurements of renal blood flow began. After the renal blood flow reached a steady state, the test compound was administered orally and changes in the renal blood flow were observed up to 9 hours. The test compound was used in doses that reduce blood pressure by 50 mmHg. The results are shown below in table. 8.

 As can be seen from the table. 8, each of the compounds of examples 2, 21, 33, 36, and 47 has a more potent activity in increasing renal blood flow than the drug selected for comparison.

 Test Example 4. Acute toxicity.

The test compound is suspended in a 1% (w / v) aqueous solution of methylcellulose and orally administered to three male mice in a single dose of 2 g / kg and survival and general condition are observed for 14 days to obtain an LD ₅₀ value. The results are shown below in table. 9.

 Thus, each of the compounds of examples 1, 2 and 33 show high safety.

 Test Example 5. Antianginal activity.

 The tests were carried out in accordance with the method of Hiramatsu et al. (Japanese Journal of Pharmacology, Vol. 20, p. 313 (1970)).

 ECG electrodes were attached to the extremities of male HOS-Donryu rats (weight 300-350 g) when anesthetized with sodium pentobarbital (50 mg / kg, extra-abdominal) and 11 leads of an electrocardiogram were recorded. A cannula for measuring blood pressure was inserted into the left femoral artery, and a cannula for administering the drug was injected into the left femoral vein. 30 minutes after administration of the compound of Example 47 and 5 minutes after administration of nifedipine or chromacalim, 0.5 U / kg of vasopressin was administered intravenously (Sigma Chemical Company). An ECG was then recorded every 30 s for 5 minutes to observe a decrease in the ST segment. The control group was given a solvent for the drug (a solution in which 5% dimethyl sulfoxide, 5% polyethylene glycol 200 and 1% cremophor were dissolved in physiological saline). The decrease in the ST segment (ΔμV) obtained every 30 s was connected by a straight line and the area surrounded by the final curve (S value; μV / min) was chosen as the degree of reduction for 5 min. Each test compound was administered at a dose that lowers blood pressure by 30 mm Hg column.

 As shown in the table. 10, the compound of Example 47 significantly reduces the S value, effectively reduces ST depression, and thus shows anti-religious activity.

 Control Example 6. Relaxation activity in relation to relaxation of the guinea pig trachea.

 Male guinea pigs were killed by bleeding and the trachea was excised. Tracheal preparation was performed as described by Takagi et al. (Chemical Pharmacological Bull., Vol. 6, pp. 716-720 (1958)).

The prepared trachea was placed in an organ bath filled with a Tyrode solution (37 ^° C. with aeration of 95% O ₂ /5% CO _{2 with} mixed gas). Tracheal response was measured isometrically using an EF-601G transducer (manufactured by Nihon Kagyo Co., Ltd.) and recorded on an R-64GP recorder (manufactured by Rika benki Co., Ltd.). The initial pressure in the prepared trachea was established at a content of 1 g after balancing the preparation after 60 minutes, in order to cause contraction, 30 mmol of potassium chloride was added. After reduction, when the pressure reached a plateau, the test compound was added. For comparison, chromakalim was used, which is known to have relaxing activity for smooth bronchial muscles (Japanese Journal of Pharmacology, Vol. 56, pp. 13-21 (1991)).

Relaxing activity was expressed as the concentration inducing 50% relaxation (EC ₅₀ ), taking relaxation of 10 ^-8 g / ml of isoproterinol (Sigma Chemical Company) as 100%. The results are shown in table. eleven.

 Each of the compounds of examples 23, 29 and 32 exhibit greater potential activity in the relaxation of the tracheal smooth muscle than chromakalim.

 Despite the fact that the invention is described in detail and with reference to specific examples, it will be obvious to any qualified specialist that it is possible to make various changes and modifications to the invention without changing the essence and scope of the invention.

 In the accompanying materials of the comparative experiment, the compounds of the invention used here are (1-1) DY-9708, (2-1) DX-9015 (racemate) and DX-9348 (optical resolution compound), (3-1) DX-9275 ( racemate) and DY-9535 (optical resolution compound), and the compounds used here as analog compounds are (1-2) EMD-NH, (2-2) EMD-57283 (racemate) and EMD-57283 ( compound with optical resolution and (3-2) EMD-Bzl (racemate) and EMD-Bzl (compound with optical resolution) The structural formulas of these tested compounds are presented at the end of the description.

 From the above comparison results, it can be seen that the antihypertensive activity of the compounds of the invention is approximately equal to the activity of the analog compounds, but the compounds of the invention are much superior to the analog compounds in terms of reducing the side effect of increasing heart rate. Thus, the superiority of the compounds of the invention over analog compounds is also evident from the numbers of comparative data of the maximum increase in heart rate (%).

 A comparative experiment was performed in the same manner as in the test examples above.

 Formulation Example 1.

The compound of example 47 - 0.1 mg
Lactose - 63 mg
Corn Starch - 16 mg
Magnesium Stearate - 0.9 mg - ---- - 80 mg
The compound of example 47, lactose and corn starch are mixed uniformly and crushed in the wet state using starch as a binder. Then magnesium stearate is added and the composition is compressed to form tablets.

тFormulation Example 2. Ampoules are filled with the following ingredients, which, after sealing the ampoules by sealing, are sterilized at 115 ^° C. for 30 minutes:
Composition (per 1 ml)
The compound of example 47 - 50 μg
Sodium Chloride - 9 mg
Distilled Water for Injection - Add. up to 1 ml
The compound of example 47 DY-9709 has the structural formula:

t

Claims (9)

1. Derivatives of diazabicycloalkenes of the general formula I:

where R ¹ represents a group of formula (II) or (III)

where R ¹¹ and R ¹² each represents a lower alkyl group, or taken together they form a lower alkylene group;
R ¹³ is a hydroxyl group, a lower acyloxy group;
R ¹⁴ is a hydrogen atom or a lower alkyl group;
A is a nitrogen atom or C-R ¹⁶ ,
where R ¹⁶ represents a hydrogen atom, cyano, nitro, trifluoromethoxy, pentafluoroethyl, sulfonyl optionally substituted with aryl, carbamoyl methyl or sulfamoyl;
R ¹⁵ is hydrogen, nitro;
R ²¹ and R ²² each represents lower alkyl;
R ²³ is hydroxyl;
R ²⁴ and R ²⁵ each is a hydrogen atom;
X is an oxygen atom or NR ³¹ , where R ³¹ is hydrogen;
R ² is hydrogen, lower alkenyl, lower alkynyl, lower alkyl, optionally substituted with a group selected from a lower alkoxy group, hydroxy group, cyano group, alkylcarbonylamino group, amino group, carbamoyl, pyridyl, lower alkoxycarbonyl, phenyl, or R ² optionally substituted lower alkylphenyl or more phenyl substituents are independently selected from sulfamoyl group, halogen atoms, lower alkyl, CN, OH, lower alkoxy;
R ³ and R ⁴ each is a hydrogen atom or lower alkyl;
n = 1,
or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that R ¹ represents a group represented by formula (II). 3. The compound according to p. 1, characterized in that R ¹ represents a group represented by formula (II), where A represents CR ¹⁶ ; X represents an oxygen atom; n represents 1. 4. The compound according to claim 1, characterized in that it is an optically active compound represented by the formula (Ia), (Ib), (Ic) or (Id) or their racemate, where R ² , R ¹³ , R ¹⁴ , R ¹⁵ , A, X and n are defined in claim 1. 5. A pharmaceutical composition having antihypertensive and anti-anginal activity, activity against potassium metabolism, increased renal blood flow and relaxation of the smooth muscle of the trachea, including a diazabicycloalkene compound as an active component and target additives, characterized in that it contains the specified compound represented by formula (I) :

where R ¹ , R ² , R ³ , R ⁴ , X and n are defined in claim 1, in an effective amount.  6. The pharmaceutical composition according to claim 5, characterized in that the active compound is a compound represented by the formula (Ia), (Ib), (Ic) or (Id) or their racemate as defined in claim 4.  7. The pharmaceutical composition according to claim 5, having an antihypertensive effect.  8. The pharmaceutical composition according to claim 5, having action against angina pectoris.  9. The pharmaceutical composition according to claim 5, having an anti-asthma effect.

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